The malignant transformation of melanocytes, pigment producing cells, leads to the generation of melanoma. Cutaneous melanoma is the most lethal form of skin cancer and one of the fastest increasing cancers in the U.S. Melanomas are highly metastatic and current therapeutic interventions are not very effective. It is well established that the formation and progression of melanoma are influenced by genetic and environmental factors, as well as alterations in tumor-host interactions. Genetic studies have identified INK4a/ARF at chromosome 9p21 as a melanoma susceptibility locus. Amongst the environmental factors, exposure to the ultraviolet (UV) spectrum of solar radiation is considered to have a casual role in the majority of melanomas. The G-coupled receptor Endothelin receptor b (Ednrb) is considered a melanoma progression marker, and in vitro data suggest that its ligand, Endothelin 3 (Edn3), can alter the expression of adhesion molecules in melanoma cells. The goal of this study is to create a novel UV-dependent mouse model of melanoma based on the over-activation of the endothelin signaling pathway to address the functional relationship among UV, genetic factors and tumor-host interactions in melanoma pathogenesis. We will use an inducible transgenic mouse model we generated and characterized that produces excessive Edn3 throughout development, leading to the accumulation of large numbers of melanocytes in the skin of adult mice where they are not normally found. This condition is a result of a dramatic increase in the proliferation of precursors, which could also serve as the basis for melanocytic tumor formation. We will (1) evaluate whether a combination of neonatal UV exposure and the over-activation of the endothelin signaling pathway is sufficient for the generation of metastatic melanoma and (2) test for a role of ink4a/arf in UV-induced melanoma formation and progression in the Edn3 transgenic mice. The development of this new mouse model of melanoma has the potential to contribute to a better understanding of the complex ethnology of this disease and serve as a tool for the evaluation of effective preventive and therapeutic regimens.